Control Dominating Subclones for Managing Cancer Progression and Posttreatment Recurrence by Subclonal Switchboard Signal: Implication for New Therapies

Abstract

In contrast to hematological malignancies, meaningful improvements in survival statistics for patients with malignant brain tumors have not been realized in >40 years of clinical research. Clearly, a new medical approach to brain cancers is needed. Recent research has led to a new concept that needs to destroy all cancer subclones to control the cancer progression. However, this new concept fails to distinguish the difference between dominating subclones and dormant subclones. Here, we address the issue of clonal switch and emphasize that there may be one or more than one dominant clones within the tumor mass at any time. Destructing one dominant clone triggers activating other dormant subclones to become dominating subclones, causing cancer progress and post-treatment cancer recurrence. We postulate the concept of subclonal switchboard signaling and the pathway that involved in this process. In the context of stem cell and development, there is a parallel with the concept of quiescent/dormant cancer stem cells (CSC) and their progeny, the differentiated cancer cells; these 2 populations communicate and co-exist. The mechanism with which determines to extend self-renewal and expansion of CSC is needed to elucidate. We suggest eliminating the "dominating subclonal switchboard signals" that shift the dormant subclones to dominating subclones as a new strategy.

Tissue Elasticity Bridges Cancer Stem Cells to the Tumor Microenvironment Through microRNAs: Implications for a ″Watch-and-Wait″� Approach to Cancer

“…3 in [2]). The endpoint will be if humans need to live with cancer, they need to guard cancer stem cell dormancy [80] for a lifetime.…”

“…Some chemically modified miRNA-targeting antisense oligonucleotides equipped with in vivo local delivery strategies are on the clinical development of miRNA-targeting therapeutics [79]. Such miRNAs specific blockade of miRNAs signaling can serve as cancer subclonal switching board management [80], effectively keeping certain cancer subclones in the sleep stage (dormant state) so that we can exercise “watch-and-wait” approach to cancer. This concept is directly supported by Liu and colleagues’ report showing that while miR-34a, a p53 target, underexpressed in CD44+ prostate cancer cells, enforced expression of miR-34a in CD44+ prostate cancer cells inhibits clonogenic expansion, tumor regeneration, and metastasis [81, 82].…”

The priming induction regimen of HAG as a low dose chemotherapy strategy in AML clonal evolution

“…There is increasing evidence to show that a low(er) dose instead of an MTD therapy can maintain a minimum tumor burden, which in turn, may restrain the proliferation of the most resistant clones. A recent study indicated that the priming induction regimen might also help to prevent the quiescent cancer stem cells (CSC) to become activated and cause tumor progression and post-treatment cancer relapse [9]. Moreover, low dose chemotherapy is presumed to have less impairment on the bone marrow microenvironment and immune system.…”

Training stem cells for treatment of malignant brain tumors

“…However, survival in solid tumors has not improved since the 1970s. New studies revealed that unexpected factors such as intratumoral heterogeneity [1] and clonal evolution force us to realize that classical therapies cannot fully address the tumor subclonal switch mechanism that allow tumors to escape therapy [2] . This includes chemotherapy drug temozolomide-driven evolution of recurrent glioma [3] into a restricted subclonal cell population of drug-resistance [4] .…”

“…These side effects result from the cumulative effects of pre-treatment injury caused by the growing tumor, the adverse impact of surgery and from adjuvant therapeutics (chemotherapy and radiation therapy) [21] . The surgical removal of the initial tumor followed with adjuvants (radiation plus chemotherapy) may awaken the dormant clones of the primary tumor and these cells then grow to form a secondary tumor (Figure 1) as the dormant cells go through switchboard signaling to become dominate clones of cancer [2] . These glioma residues grow back, leading to recurrent incurable and metastatic cancer.…”